Inhibition and treatment of prostate cancer metastasis

Abstract

The present invention provides compounds and methods of inhibiting and treating metastatic prostate cancer. The compounds include MEK4 inhibitors. In another aspect the invention provides methods of identifying inhibitors of metastatic prostate cancer by screening for inhibitors of MEK4.

1 - 19 . (canceled) 
     
     
         20 . A method of inhibiting MEK4 in vitro, comprising:
 administering a compound having formula:   
       
         
           
           
               
               
           
         
         to a MEK4 enzyme in vitro; wherein A is C═O, CHOH, C═NR, or CH 2 ; X is O or NH; Y is O, NH, CR 9 ═CR 10 , or CH═N; Z is OH, OCH 3 , halogen, or H provided that one of R 7  or R 8  is OH or OCH 3 ; the dashed line represents an optional double bond; R is H or a substituted or unsubstituted alkyl group; R 1  is selected from the group consisting of H and substituted or unsubstituted alkyl groups; R 2  is selected from the group consisting of H, OH, F and Cl; or is absent when the optional double bond is present; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9  and R 10  are each independently selected from the group consisting of OH, F, Cl, Br, I, CN, NO 2 , COOR, CONH 2 , and substituted and unsubstituted alkyl and alkoxy groups. 
       
     
     
         21 . The method of  claim 20 , further comprising the step of detecting MEK4 enzyme activity. 
     
     
         22 . The method of  claim 21 , wherein said MEK4 enzyme activity comprises detecting activity of a MEK4 enzyme pathway member. 
     
     
         23 . The method of  claim 22 , wherein said MEK4 enzyme pathway member is selected from the group consisting of: p38 MAPK, MAPK APK2, HSP 27, or MMP-2. 
     
     
         24 .- 28 . (canceled) 
     
     
         29 . A pharmaceutical preparation comprising a compound having formula: 
       
         
           
           
               
               
           
         
         wherein A is C═O, CHOH, C═NR, or CH 2 ; X is O or NH; Y is 0, NH, CR 9 ═CR 10 , or CH═N; Z is OH, OCH 3 , halogen, or H provided that one of R 7  or R 8  is OH or OCH 3 ; the dashed line represents an optional double bond; R is H or a substituted or unsubstituted alkyl group; R 1  is selected from the group consisting of H and substituted or unsubstituted alkyl groups; R 2  is selected from the group consisting of H, OH, F and Cl; or is absent when the optional double bond is present; R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9  and R 10  are each independently selected from the group consisting of OH, F, Cl, Br, I, CN, NO 2 , COOR, CONH 2 , and substituted and unsubstituted alkyl and alkoxy groups; wherein said compound is not genistein. 
       
     
     
         30 . The composition of  claim 29  wherein, if Z is H, one of R 7  or R 8  is OH or OCH 3 . 
     
     
         31 . The composition of  claim 29 , wherein R 3 , R 4 , R 5 , and R 6  are each H. 
     
     
         32 . The composition of  claim 29 , wherein Z is OCH 3 , halogen, or H. 
     
     
         33 . The pharmaceutical composition of  claim 29 , wherein said compound is selected from the group consisting of 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         34 . A composition comprising a compound selected from the group consisting of 
       
         
           
           
               
               
           
         
       
       and a compound described by the following formula: 
       
         
           
           
               
               
           
         
         including salts, esters, and prodrugs thereof; 
         including both R and S enantiomeric forms and racemic mixtures thereof; 
         wherein A is selected from the group consisting of O, C═O, CHOH, C═NR, and CH2; 
         wherein X is selected from the group consisting of C═O, O, and NH; 
         wherein Y is selected from the group consisting of O, NH, CR 9 ═CR 10 , and CH═N; 
         wherein Z is selected from the group consisting of OH, OCH 3 , halogen, and H provided that one of R 7  or R 8  is OH or OCH 3 ; 
         wherein R is selected from the group consisting of H and a substituted or unsubstituted alkyl group; 
         wherein R 1  is selected from the group consisting of H, C═O, and substituted or unsubstituted alkyl groups; 
         wherein R 2  is absent or is selected from the group consisting of H, OH, F and Cl; 
         wherein R 3 , R 4 , R 5 , R 6 , R 7 , R g , R 9  and R 10  are each independently selected from the group consisting of OH, F, Cl, Br, I, CN, NO 2 , COOR, CONH 2 , and substituted and unsubstituted alkyl and alkoxy groups; and 
         wherein R is, at each occurrence, independently selected from the group consisting of hydrogen, a substituted or unsubstituted alkyl group, and a substituted or unsubstituted alkoxy group. 
       
     
     
         35 . The composition of  claim 33 , wherein said compound is selected from the group consisting of